ABSTRACT Obesity is a major health problem associated with a significant increase in metabolic syndrome, diabetes, and heart disease. Thus, obesity demands an in-depth understanding of its causes at the cellular, molecular and organismal level. In an exciting new development, identification of human mutations in SH2B1 that associate with profound childhood obesity implicate the scaffold protein SH2B1 as a critical regulator of body weight, in- sulin sensitivity and behavior. There is a fundamental gap in our understanding of how SH2B1 regulates neural circuitry that maintains energy homeostasis and how human obesity mutations in SH2B1 disrupt that circuitry and contribute to obesity. Our long-term goal is to identify novel key signaling proteins and/or gene regulatory events that are regulated by SH2B1, critical for establishing and maintaining neural circuits important for nor- mal feeding behavior and energy balance, can be targeted for therapeutic intervention for obesity, insulin- resistance and/or maladaptive behavior. Primary neurons, novel mouse models and cultured cells will be used to test the central hypothesis that SH2B1 is crucial for the establishment and maintenance of neural circuits important for normal feeding behavior and energy balance. Mechanistically, SH2B1 serves as a scaffold pro- tein that enhances signaling pathways at the plasma membrane and cycles to the nucleus, both are required for regulating gene transcription and neurite outgrowth. Human disease mutations impair a subset of these re- sponses. The specific aims are: 1) Determine neurotrophic ligand signaling pathways regulated by SH2B1 and impaired by the human mutations; 2) Determine how nuclear SH2B1, which is required for neurite outgrowth, enhances gene expression and the human mutations impair that enhancement; and 3) Define the role for SH2B1 in neural circuit formation and transcription in hypothalamic neurons implicated in energy balance. This research is innovative because: 1) SH2B1 was recently implicated as a human obesity gene; 2) newly identi- fied SH2B1 mutations provide powerful tools to study the causes of obesity; 3) the concept of coordinating an integrated response to neurotrophic ligands by movement of scaffold proteins between the plasma membrane and the nucleus is novel; and 4) many of the proposed techniques and mouse models are cutting edge, includ- ing CRISPR/Cas9 technology to delete or edit Sh2b1, mouse models to study the effect of SH2B1 on neuronal projections, studying gene expression within the small population of LepRb neurons in the hypothalamus, and the unique Sh2b1P322S mouse that enables study of the impact of a human SH2B1 mutation in intact mice and isolated neurons. The proposed research is significant because it will provide critical insight into the cellular and molecular mechanisms by which SH2B1 and the human mutations affect the function of neurons, including those that regulate body weight, and how complex, multi-protein based signals are coordinated between plas- ma membrane receptors and the nucleus. This insight will advance our understanding of neuron function and identify potential new therapeutic targets for obesity, insulin resistance and/or maladaptive behavior.